Ras oncogenes are the most frequently identified activated oncogenes in human tumors. Transformed protein Ras is involved in the proliferation of cancer cells. Ras must be farnesylated before this proliferation can occur. Farnesylation of Ras by farnesyl pyrophosphate is effected by farnesyltransferase. Inhibition of farnesyltransferase and, thereby, of farnesylation of the Ras protein, blocks the ability of transformed cells to proliferate. Therefore, there is a need for compounds which are inhibitors of farnesyltransferase.
The large scale production of farnesyltransferase inhibitors requires chemical syntheses which avoid complicating factors such as use of high cost reagents, chemicals which require special handling, lengthy multi-step synthetic sequences, chromatography of intermediates, and low-yielding steps. An effective strategy to lower the cost associated with multi-step processes is the reduction in the number of steps required to complete the synthesis by combining several steps into a "single pot," thereby forming a continuous process. However, running multiple steps in a single reaction vessel or without purification of intermediates poses a challenge due to competing side reactions, solvent incompatibilities, and purification difficulties.
The instant invention discloses a novel synthesis of farnesyltransferase inhibitors which allows multiple reaction steps in a single reaction vessel without isolation of intermediates. In addition, this invention provides a process that avoids costly chromatography of the intermediates and products.